This invention relates to aqueous crystalline suspensions of 17-tertiary steriod glycoesters and to glycobenzoates.
The pharmacological activity of steriods lasts only for a short time in general. In order to be used as contraceptives, steriods must be administered daily as a result.
Attempts have been made to prolong their duration of activity by esterification. Thus, it is known that a protractive effect can be achieved by esterifying biologically active steriod alcohols with long-chain, branched or cyclic fatty acids. An additional depot effect is frequently obtained by adding the active agent to a carrier compound that releases the active agent with retardation. One injectable depot contraceptive, for example, is norethisterone enanthate in an oily solution. At a dosage of 200 mg of norethisterone enanthate in 1 ml of castor oil/benzyl benzoate in a ratio of 6:4, the effectiveness lasts about 12 weeks. However, it has been found that the number of pregnancies while under the effect of norethisterone enanthate is somewhat larger than in the case of daily oral ingestion of a tablet. Moreover, undesired pregnancies occur, in particular, shortly before the end of the injection interval.
Investigating the serum steroid concentration after a single intramuscular injection of 200 mg of norethisterone enanthate in human subjects, a high initial concentration or norethisterone has been found. This drops initially very rapidly and then continues to decrease gradually (Contraception 24: 15-17 [1981]). In order to maintain a specific higher level of norethisterone over a period of 12 weeks, it is necessary to administer dosages or norethisterone enanthate that are too high physiologically.
High initial concentrations of medroxyprogesterone have also been measured after injection of medroxyprogesterone acetate as an aqueous crystalline suspension (J. Clin. Endrocinol. Metab. 44: 32-38 [1977]).
Tertiary 17-acylglycol esters are described in German Pat. No. 2,558,076, produced for example, by esterifying the steriod alcohol with glycolic acid and further esterification of the primarily obtained glycol ester with a long-chain carboxylic acid. Another preparation approach is the reaction of the steriod alcohol in one step with the desired acylglycoyl chloride. By interposing glycolic acid, the objective is attained that the tertiary 17-ester, in two stages, is almost completely saponified. The stepwise construction of the ester, however, not only results in an almost complete cleavage of the ester and exploitation of the active agent, but also in a ready availability of the active agent. Directly after injection, a relatively large amount of active agent is released for a few days, which can lead to side effects.